Novel oxidative pathway targets microglia in Alzheimer's disease

Abstract Alzheimer's disease is the most common dementia characterized by progressive cognitive decline. By estimates, Alzheimer's disease affects more than one-third of the population over 85, posing a substantial socioeconomic burden. There is an apparent lack of understanding of the molecular mechanisms of Alzheimer's disease and reported problems with animal models. These obstacles prevent the development of new therapeutic strategies, especially their translation to human patients. This proposal is based on molecular and cellular evidence and an analysis of human Alzheimer's disease cases. It bridges several aspects of Alzheimer's disease pathology: discovery of unique oxidative stress pathway, new aspects of microglial biology and dysfunction, and basic mechanisms of cell adhesion/phagocytosis in the context of disease. We will answer how exactly oxidation causes microglial dysfunction in Alzheimer's disease and how to prevent/inhibit their detrimental consequences. Based on our pioneering preliminary studies, we propose that oxidative stress targets important proteins in microglia responsible for phagocytosis, leading to deficient phagocytosis and microglia overactivation in Alzheimer's disease. Therefore, we will focus on the mechanisms of this damage and its prevention in Alzheimer's disease and other neurodegenerative pathologies. We will develop a new intervention approach (compounds neutralizing oxidative stress) and uncover new specific targets for the treatment of Alzheimer's disease.